Genetics
SREBP-1 activates the CETP gene in transgenic mice but is not required for its cholesterol-driven up-regulation (J Biol Chem 1998)
Original title: Sterol regulatory element binding protein-1 activates the cholesteryl ester transfer protein gene in vivo but is not required for sterol up-regulation of gene expression
In human CETP transgenic mice, deletional analysis had localized the cholesterol-response region of the CETP promoter to a tandem repeat resembling the sterol regulatory element of the HMG-CoA reductase gene. Gel shift assays showed SREBP-1 and YY-1 bind this element, and point mutations MUT1 and MUT2 reduced binding of SREBP-1 alone or of both factors. MUT1- and MUT2-CETP transgenic mice still showed normal induction of plasma CETP activity on high-fat, high-cholesterol diets, matching natural flanking region mice, and MUT1/MUT2 promoter-reporter constructs remained sterol-inducible in adipocyte cell lines. Crossing SREBP-1 transgenic mice onto the natural flanking region CETP background produced a 3-fold rise in plasma CETP activity, but no significant change occurred in MUT1-CETP/SREBP-1 crosses, showing SREBP-1 transactivates CETP through this element in vivo without being required for sterol-driven CETP induction.
Original abstract
The plasma cholesteryl ester transfer protein (CETP) plays a central role in high density lipoprotein metabolism and reverse cholesterol transport. Plasma CETP levels are increased in response to dietary or endogenous hypercholesterolemia as a result of increased gene transcription in liver and periphery. Deletional analysis in human CETP transgenic mice localized this response to a region of the proximal promoter which contains a tandem repeat of the sterol regulatory element (SRE) of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. The purpose of the present study was to evaluate the role of the SRE-like element in CETP promoter activity. Gel shift assays using CETP promoter fragments containing these elements showed binding of the transcription factors, sterol regulatory element-binding protein-1 (SREBP-1) and Yin Yang-1 (YY-1). Point mutations in the SRE-like element, designated MUT1 and MUT2, resulted in decreased binding of SREBP-1 (MUT1) or SREBP-1 and YY-1 (MUT2). To determine the in vivo significance of this binding activity, CETP transgenic mice were prepared containing these promoter point mutations. MUT1 and MUT2 transgenic mice expressed CETP activity and mass in plasma. In response to high fat, high cholesterol diets, both MUT1-CETP and MUT2-CETP transgenic mice displayed induction of plasma CETP activity similar to that observed in natural flanking region (NFR) CETP transgenic mice. Moreover, in stably transfected adipocyte cell lines, MUT1 and MUT2 CETP promoter-reporter genes showed significant induction of reporter activity in response to sterols. To evaluate transactivation by SREBP-1, NFR- and MUT1-CETP transgenic mice were crossed with SREBP-1 transgenic mice. Induction of the SREBP transgene in the liver with a low carbohydrate diet resulted in a 3-fold increase in plasma CETP activity in NFR-CETP/SREBP transgenic mice, but there was no significant change in activity in MUT1-CETP/SREBP transgenic mice. Thus, SREBP-1 transactivates the NFR-CETP transgene in vivo, as a result of interaction with the CETP promoter SREs. However, this interaction is not required for positive sterol induction of CETP gene transcription. The results suggest independent regulation of the CETP gene by SREBP-1 and a distinct positive sterol response factor.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.